Biology subjects

Sierralta, J.

Publications and source records attributed to Sierralta, J..

3 recordsLinked to original sources

bioRxiv2023

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models

Brains are highly metabolically active organs, consuming 20% of an organisms energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, its unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimers disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

neuroscience↗

bioRxiv2022

Drosophila Atlastin regulates synaptic vesicle mobilization independent of Bone Morphogenetic Protein signaling

Motor neurons are highly dependent on membrane trafficking, in which the endoplasmic reticulum (ER) and its contact sites with endosomes, confer the ER the role of a long-distance communicator. Atlastin (Atl), a large GTPase located on the ER membrane is required for its function and its tubular structural dynamics. Atl also downregulates, by a yet unknown mechanism, the BMP (Bone Morphogenic Protein) pathway. In humans, Atl mutations are the second more common cause of Hereditary Spastic Paraplegia (HSP), a genetic disease characterized by spasticity of the lower extremities. Here, we explore the molecular basis of Atl-dependent defects on synaptic vesicle (SV) traffic in Drosophila under the hypothesis that those defects are the direct consequence of the atl-knock-down and not of the Atl-dependent BMP signaling upregulation. Motor neuronal knockdown of atl (Atl-KD) leads to an increase in synaptic and satellite bouton number similar to the increase in BMP signaling activity (TKV-CA). Neuronal Atl-KD also associates to a reduction in the boutons of the abundance of the SV markers CSP (Cysteine string protein) and VGLUT (vesicular glutamate transporter) as well as in TKV-CA larvae, both phenotypes are suppressed by decreasing the function of BMP receptor wishful thinking expressing one copy of the mutant receptor (wit /+). Surprisingly, we determined in Atl-KD larvae an increase in the CSP peripheral density and distribution, dependent on synaptic stimulation, that was not replicated in Tkv-CA larvae, suggesting that there could be differences in the mechanisms that underlie the reduction in CSP abundance. Additionally, we determined that Atl-KD associates to an increase in FM 1-43 unload but not in TKV-CA larvae. Moreover, one copy of wit was not able to suppress the FM-143 in Atl-KD larvae (Atl-KD, wit), supporting that BMP signaling does not participate in this phenotype. Together with the stimuli-dependent changes in the SV distribution and dynamics determined in Atl-KD larvae, we measured an increase in Rab11/CSP colocalization, suggesting changes in SV traffic through late recycling endosomes. Together our results suggest a mechanism by which the loss of an ER structuring protein in the motor neuron could, through its role in regulating SV and endosomal trafficking, explain defects in SV accumulation and synaptic dysfunction.

cell biology↗

bioRxiv2019

Monocarboxylate Transport In Drosophila Larval Brain During Low And High Neuronal Activity

The transport of lactate and pyruvate between glial cells and neurons plays an important role in the nervous system metabolic coupling. However, the mechanisms and characteristics that underlie the transport of monocarboxylates (MC-T) in vivo are poorly described. Here we use Drosophila expressing genetically-encoded FRET sensors to provide an ex vivo characterization of the MC-T in motor neurons and glial cells from the ventral nerve cord. We show that lactate/pyruvate transport on glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient towards neurons. Moreover, our results show that under increased activity lactate and pyruvate rise on motor neurons and suggest that this depends on the transfer of lactate from glial cells mediated in part by the previously described MC transporter Chaski, giving support to the in vivo glia to neurons lactate shuttling during activity.

neuroscience↗